A subset of dysregulated metabolic and survival genes is associated with severity of hepatic steatosis in obese Zucker rats
A subset of dysregulated metabolic and survival genes is associated with severity of hepatic steatosis in obese Zucker rats
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DOI：
10.1194/jlr.m001966
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发表时间：
2010-03-01
影响因子：
6.5
通讯作者：
Ochoa, Begona
中科院分区：
文献类型：
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作者：
Buque, Xabier;Jose Martinez, Maria;Ochoa, Begona
我们旨在描述与肥胖相关脂肪肝的脂肪堆积以及肝细胞易损性相关的主要异常情况。我们对来自肥胖的胰岛素抵抗型祖克大鼠（包括轻度至重度肝脂肪变性）肝脏的分离原代肝细胞以及年龄匹配的瘦同窝大鼠进行了功能分析和比较转录组学研究，以寻找与慢性肝脂肪变性相关的新基因。在测试的基因组中，1.6%被确定与脂肪变性相关。过表达的基因主要涉及初级代谢（100%）、信号传导以及防御/急性期（约70%）；解毒、类固醇和硫代谢（约65%）以及细胞生长/增殖和蛋白质合成/转化（约70%）基因被下调。参与从头脂肪生成、脂肪酸和甘油酯摄取与合成以及乙酰辅酶A和辅因子供应的关键基因的过表达，与肝脏脂肪生成增强以及富含甘油三酯的大极低密度脂蛋白的产生同时发生。基因表达的最大变化出现在编码生脂苹果酸酶（增加多达7倍）和细胞间相互作用的钙黏蛋白17（减少多达8倍）的基因中。在经过验证的基因中，脂肪酸合酶、硬脂酰辅酶A去饱和酶1、脂肪酸转位酶/CD36、苹果酸酶、胆固醇 - 7α - 羟化酶、钙黏蛋白17和过氧化物酶体增殖物激活受体α与肝脂肪变性的严重程度显著相关。总之，在肥胖的胰岛素抵抗型大鼠中，代谢和生存相关基因的表达失调伴随肝脂肪变性，并且可能使脂肪变性的肝细胞在进展性非酒精性脂肪性肝病中更易受到细胞损伤。 - 布克，X.，M. J. 马丁内斯，A. 卡诺，M. E. 米基莱纳 - 科利纳，C. 加西亚 - 蒙松，P. 阿斯皮丘埃塔，B. 奥乔亚。一组失调的代谢和生存基因与肥胖祖克大鼠肝脂肪变性的严重程度相关。《脂质研究杂志》2010年。51卷：500 - 513页。
We aimed to characterize the primary abnormalities associated with fat accumulation and vulnerability to hepatocellular injury of obesity-related fatty liver. We performed functional analyses and comparative transcriptomics of isolated primary hepatocytes from livers of obese insulin-resistant Zucker rats (comprising mild to severe hepatic steatosis) and age-matched lean littermates, searching for novel genes linked to chronic hepatic steatosis. Of the tested genome, 1.6% was identified as steatosis linked. Overexpressed genes were mainly dedicated to primary metabolism (100%), signaling, and defense/acute phase (similar to 70%); detoxification, steroid, and sulfur metabolism (similar to 65%) as well as cell growth/proliferation and protein synthesis/transformation (similar to 70%) genes were downregulated. The overexpression of key genes involved in de novo lipogenesis, fatty acid and glycerolipid import and synthesis, as well as acetyl-CoA and cofactor provision was paralleled by enhanced hepatic lipogenesis and production of large triacylglycerol-rich VLDL. Greatest changes in gene expression were seen in those encoding the lipogenic malic enzyme (up to 7-fold increased) and cell-to-cell interacting cadherin 17 (up to 8-fold decreased). Among validated genes, fatty acid synthase, stearoyl-CoA desaturase 1, fatty acid translocase/Cd36, malic enzyme, cholesterol-7 alpha hydroxylase, cadherin 17, and peroxisome proliferator-activated receptor alpha significantly correlated with severity of hepatic steatosis. In conclusion, dysregulated expression of metabolic and survival genes accompany hepatic steatosis in obese insulin-resistant rats and may render steatotic hepatocytes more vulnerable to cell injury in progressive nonalcoholic fatty liver disease.-Buque, X., M. J. Martinez, A. Cano, M. E. Miquilena-Colina, C. Garcia-Monzon, P. Aspichueta, and B. Ochoa. A subset of dysregulated metabolic and survival genes is associated with severity of hepatic steatosis in obese Zucker rats. J. Lipid Res. 2010. 51: 500-513.